Developing new mouse models of andropause for ADRD research

PROJECT SUMMARY/ABSTRACT Aging and AD are associated with a decline in sex hormones. Approximately 40% of men over 45-years old suffer from low androgen levels. Endocrine aging in men, termed andropause, is characterized by age-related declines in androgens (such as testosterone). These declines in androgens are associated with increased AD

risk and cognitive decline. Despite advances in menopause models, models of endocrine aging in males (andropause) have been stalled for over a century and are limited to gonadectomy. Gonadectomy causes almost a complete loss of androgens, and thus does not accurately mimic reduced androgen levels observed in

andropause in men. Lack of more accurate models of andropause that more closely mimic the human hormonal profile is a critical technical gap that is severely limiting the fields of aging and dementia. Our long-term goal is to develop mouse models of dementia that more accurately reflect the hormonal environment in humans and

thus increase the translational potential of therapies that are tested in these models. The objective of this proposal is to develop two new mouse models of andropause. First, we will determine the time course of natural endocrine aging in WT mice and several mouse models of ADRD (Aim 1). Next, we will model endocrine aging

in males via gonadectomy and hormone replacement with gradual decreasing of androgen replacement over time (Aim 2). For a non-surgical model of andropause, we will determine if a reproductive toxin can be used to induce gradual androgen loss in male mice (Aim 3). For each model, we will assess aging phenotype (decreased

strength, reduced activity, increased anxiety, and impaired memory) and AD neuropathology. We predict that mice with low androgen levels will exhibit a more accelerated aging phenotype and increased AD neuropathology. This would represent the first ever models of andropause with carefully controlled, gradual

hormone loss. Without these new, improved models of andropause, the field will continue to test therapeutics for AD in male mice with an endocrine status does not match that of aging men. This hinders the translational potential of these therapies. Our new models have the potential to transform the aging field.